tbuckley/cabot-search huggingface dataset:
Determining the role of uremic toxins on cardiac electrophysiology and pro-arrhythmia during chronic kidney disease
Authors: WB Van Ham, A Bossu, MJC Houtman, CM Cornelissen, MA Vos, TAB Van Veen
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Young Talent Programme, CVON RECONNECT Introduction Chronic kidney disease (CKD) is represented by a diminished filtration capacity of the kidneys. End stage renal disease patients need dialysis treatment to remove waste and toxins from the circulation. However, endogenously produced uremic toxins (UTs) cannot always be filtered during dialysis. UTs are one of the CKD-related factors already linked to maladaptive and pathophysiological remodeling of the heart. Importantly, 50% of the deaths in dialysis patients is cardiovascular related, with sudden cardiac death predominating. However, the mechanisms responsible still remain poorly understood. Purpose To assess the potentially increased pro-arrhythmic risk of pre-identified UTs at clinically relevant concentrations: 1) acutely in isolated adult dog ventricular cardiomyocytes (ADCMs) and human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), 2) chronically in iPSC-CMs and 3) both conditions in human embryonic kidney (HEK) cells transfected with constructs that generate different ion channels, using optical and manual electrophysiological in vitro approaches. Methods and results Using the voltage sensitive membrane dye FluoVolt and manual patch clamp, action potential duration (APD) prolongation, considered as a pro-arrhythmic parameter, was assessed in ADCMs and iPSC-CMs. Acute exposure of indoxyl sulfate (IS), kynurenine (KYN) or kynurenic acid (KYNA) induced no alterations in APD in ADCMs and iPSC-CMs. iPSC-CMs, although having rather immature electrophysiological characteristics, showed significant APD prolongation when exposed chronically (48h) to those UTs. Manual patch clamp on HEK293 cells was performed to investigate individual ion currents to reveal underlying mechanisms. The repolarizing current IKr, often most sensitive and responsible for APD alterations, was not acutely affected by IS, KYN, or KYNA. However, chronic exposure (48h) to IS or KYNA significantly decreased IKr at clinically relevant concentrations. Finally, the protein level of the ion channel conducting IKr was determined in HEK293 cells, to further unveil the mechanism behind the effects of UTs on channels conducting IKr. Chronic exposure (48-72h) of the three UTs decreased total ion channel expression at pathological concentrations, which could be responsible for the decreased IKr and prolonged APD. Conclusion The results show the proof of concept to identify potentially pro-arrhythmogenic UTs and their mode of action, allowing the provision of a clinically relevant overview of (patho)physiological concentrations of UTs in both acute and chronic exposure.
Rapid screening of SARS-CoV-2 inhibitors via ratiometric fluorescence of RBD–ACE2 complexes in living cells by competitive binding
Authors: Lu Miao, Wei Zhou, Chunyu Yan, Yuebin Zhang, Qinglong Qiao, Xuelian Zhou, Yingzhu Chen, Guangying Wang, Zhendong Guo, Jun Liu, Hailong Piao, Xia Pan, Mengxue Yan, Weijie Zhao, Guohui Li, Yueqing Li, Zhaochao Xu
Journal: Acta Pharmaceutica Sinica B (2022)
Designing and implementing an evidence-based and longitudinal implicit bias training curriculum for school of medicine members and healthcare providers.
Authors: Lauren M. Hamel, Leah M. Robinson, Marquita Chamblee, David W. Dougherty, Beena Sood
Journal: Journal of Clinical Oncology (2022)

e24136 Background: Implicit bias negatively influences decisions and communication in oncology care, and may also lead to disparities in cancer treatment and outcomes. The School of Medicine (SOM) at Wayne State University (WSU), based in the diverse yet segregated city of Detroit, Michigan, has faced the consequences of bias. Fortunately, within SOM/WSU, expertise on the problem of and solutions to implicit bias have flourished. We leveraged that expertise to design and implement a comprehensive and longitudinal implicit bias curriculum for SOM members and healthcare providers, including hematology/oncology faculty, providers, and trainees. We designed the curriculum to satisfy State of Michigan implicit bias training requirements for all healthcare providers. To date, we have implemented two modules. Prior to the second module, we received IRB-approval to recruit curriculum participants as study participants and tested effectiveness. Methods: The curriculum is comprised of 1½ hour modules offered every three months. Topics include how implicit bias influences clinical communication with a focus on the oncology care context, how structural racism influences health policy, among others. To evaluate, we utilize Kirkpatrick’s Four-Level Training Evaluation Model, to assess outcomes at 4 levels: 1. reaction, 2. learning, 3. behavior change and 4. long-term results. After obtaining passive consent from participants, we gathered effectiveness data at Levels 1 and 2. Results: We implemented two modules (How Patient and Physician Race-Based Attitudes Influence Clinical Communication &amp; Structural Racism 101: Basic Training for Doctors) in 2021 via Zoom. More than 160 people attended each module with many participants representing oncology-focused hospitals and academic departments. All participants received a certificate of participation as a part of the state requirements for implicit bias training, and CME credit. For Session 2 we asked participants to respond to a survey before (n = 106) and after (n = 35) the session assessing Levels 1 and 2. Participant evaluations (Level 1) were very positive, with many participants noting that they plan to put what they have learned into practice immediately. A common critique was the desire for more topics and more time to discuss. Findings show increased knowledge (Level 2) of structural racism (pre: 92% vs. post: 97%); spatial racism (pre: 87% vs. post: 91%); and how racism influences health policy (pre: 80% vs post: 86%). Conclusions: We successfully implemented a longitudinal implicit bias curriculum for SOM members and healthcare providers. Next steps include continuing to implement and assess the curriculum, and collecting data at Levels 3 and 4. This type of curriculum could be an important tool to decrease bias in cancer care and improve cancer care equity.
RARE-24. The use of novel<i>in vitro</i> models to study adamantinomatous craniopharyngioma disease biology and drug response
Authors: Tammy Trudeau, Eric Prince, Oscar Chatain, Keanu Chee, Eric Jackson, David Limbrick, Robert Naftel, Neil Feldstein, Gerald Grant, Kevin Ginn, Toba Niazi, Amy Smith, Lindsay Kilburn, Joshua Chern, Annie Drapeau, Sandi Lam, James Johnston, Roy Dudley, Susan Staulcup, Todd Hankinson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Challenges around the design and investigation of cell culture models of adamantinomatous craniopharyngioma (ACP) have arisen from the cellular heterogeneity of these tumors, with populations that harbor disparate requirements in culture. Novel approaches to in vitro modeling of ACP are needed. METHODS: Intraoperatively collected tumor specimens were mechanically digested and plated under conditions tailored to the cell population of interest. ACP tumor-derived fibroblasts and epithelial cells were isolated using serum-containing and keratinocyte-specific media respectively. ACP-derived epithelial cells were immortalized via SV40 virus transfection and puromycin treatment for stable cell-line generation. Cell line validation included immunofluorescence with markers appropriate for the cell population of interest. RNA sequencing of cell lines was compared to ACP transcriptome reference data. Cell typing was conducted using short tandem repeat sequencing. RESULTS: ACP fibroblasts and ACP epithelial cells maintained spindle-like and cobblestone morphologies respectively, even after 4 passages. Immunofluorescence staining confirmed high levels of Vimentin expression in ACP-derived fibroblasts, and panCK and B-catenin in ACP-derived epithelial cells. Point mutation in exon 3 of the CTNNB1 gene was identified in ACP-derived epithelial cells. CONCLUSION: Initial limits related to cell line development in ACP may be addressed through the isolation and culture-specific ACP cell populations. This experience demonstrates the maintenance of validated markers of the cell populations of interest ex vivo. While preliminary, such cell lines offer promise as tools for the identification and study of potential therapeutic vulnerabilities in ACP.
High homology of carcinomatous component and sarcomatous component in pulmonary carcinosarcoma and heterogeneity of gene expression among different patients.
Authors: Haixia Wu, Yingbo Xue, Ping Huang, Xiaoliang Wu, Xueqin Peng, Xin Liu
Journal: Journal of Clinical Oncology (2022)

e20534 Background: Pulmonary carcinosarcoma (PCS) is a rare subtype of non-small-cell lung cancer (NSCLC) which is highly aggressive and currently has no optimal treatment. Previous studies have shown that some potential markers for targeted therapy and immunotherapy have been detected in PCS patients. A few studies and cases have used microdissection to separate the carcinomatous component (CaC) and sarcomatous component (SaC) component of PCS and performed DNA-based next-generation sequencing (NGS) and confirmed that the two components are highly homologous. There are no studies yet to analyze the differences between CaC and SaC in PCSs from multiple aspects including DNA, RNA, and protein expression assays. Methods: 10 tumor tissues from 5 PCS patients were divided into CaCs and SaCs by microdissection, DNA-based NGS with a 520 gene panel, RNA-based NGS with a 115 gene panel, and Immunohistochemistry (IHC) were performed on these samples. The same type of detection results for different components of the tumors were used for comparative analysis, and the overall DNA test results of the two components were used to compare with detection data of NSCLC and lung sarcoma in the TCGA database respectively. Results: No significant differences were found between CaC and SaC at both DNA, RNA, and IHC assays. The most commonly mutated genes in this cohort of patients were TP53 (10/10, 100%), KRAS (6/10, 60%), LRP1B (5/10, 50%), RBM10, PTPRT, AKT2 (both are 4/10, 40%). Notably, all the mutated genes detected were more similar to those detected in NSCLC rather than mutated genes commonly found in sarcomas. In addition, regardless of DNA or RNA sequencing, no landmark fusion variants were detected in the four available sarcoma tissues. Single sample gene set enrichment analysis (ssGSEA) was used to analyze the RNA results of the matched CaC and SaC of the three patients, no difference in RNA expression among different types of tissues in the same patient was found, but gene expression heterogeneity among the 3 patients was very high. IHC results showed that the positive rates of PD-L1, CD3 and CD8 in the 5 CaCs were 40%, 100% and 100%, while this value was 80%, 100% and 100% in the 5 SaCs. PD-L1 showed a trend of high expression rate in SaC tissues of PCS patients. Conclusions: This study showed that the CaC and SaC tissues of the same PCS patient were both highly homologous in terms of DNA, RNA and protein expression, but the RNA expression was highly heterogeneous among different patients. The landscape of genetic alterations revealed that PCSs are molecularly more likely to arise from NSCLC rather than lung sarcomas, which suggests that for these patients, it may be suitable to choose a treatment plan for the pathological type of the carcinomatous component.
The value of systematic biopsies in screening for prostate cancer with PSA followed by MRI – results from the GÖTEBORG prostate cancer screening 2 trial
Authors: K. Kohestani, R. Arnsrud Godtman, U. Axcrona, L. Egevad, M. Hellström, A. Khatami, C-G. Pihl, J. Stranne, J. Wallström, M. Månsson, S.V. Carlsson, J. Hugosson
Journal: European Urology (2022)
Sequential immunotherapy in rare variant renal cell carcinomafinal report of UNISoN (ANZUP 1602): Nivolumab then ipilimumab + nivolumab in advanced nonclear cell renal cell carcinoma.
Authors: Ciara Conduit, Ganessan Kichenadasse, Carole A. Harris, Howard Gurney, Tom Ferguson, Francis Parnis, Jeffrey C. Goh, Michelle Frances Morris, Craig Underhill, David William Pook, Ian D. Davis, Felicia Roncolato, Michelle L. Harrison, Stephen Begbie, Anthony M. Joshua, Emma Link, Elizabeth J. Hovey, Craig Gedye
Journal: Journal of Clinical Oncology (2022)

4537 Background: Immune checkpoint immunotherapy (ICI) is active against many cancers. Many people are failed by PD1 inhibition alone, but not all patients benefit, nor require combination ICI treatment. UNISoN (NCT03177239) previously reported outcomes in people with non-clear cell renal cell carcinoma (nccRCC) receiving nivolumab (N) monotherapy, and N plus ipilimumab (I) in those whose cancers progressed after N alone. We present the final planned report. Methods: Population, Intervention, Analysis: Participants (pts) with advanced nccRCC with good performance status (ECOG 0/1) received N 240mg q2w alone (Part 1). Those with cancers refractory to N at 3 months were offered combination I (1mg/kg) + N (3mg/kg) q3w for up to 4 doses, followed by N 240mg q2w for a maximum total of 12 months of N (Part 2). UNISoN was powered to identify a clinically-relevant objective tumor response rate (OTRR) of 30% (assuming 15% was not relevant) among people receiving I+N in Part 2. Results: 85 pts with a representative spectrum of nccRCC histologies were enrolled and received N. Amongst the total population enrolled to UNISoN Part 1/2, mOS was 24 (16-28) months and 12m OS was 65% (54%-74%); of those proceeding to Part 2, the mOS was 10 (6-17) months only. Overall, 17% (10%-27%; 14/83) and 10% (3%-23%; 4/41) of pts experienced a response from N alone or I+N, respectively. 41 pts refractory to N received I+N. Overall in Part 2, the median time on treatment was 2.1 (95% CI 1.8, 2.8) months, the median number of cycles was 3; median follow-up at final analysis was 22 (16-30) months. In this population, the median PFS was 2.6 (2.2-3.8) months and 12m PFS was 11% (4%-23%). 13% (7%-22%) of patients were free of progression or death at 24 months. The primary endpoint was not met; only 80% of pts failed by N were assessable for response in Part 2. Overall tumor responses from N alone or I+N were more common in pts with papillary histology; pts with chromophobe histology had poor outcomes. No late toxicity safety signals were observed. Conclusions: Some pts with nccRCC benefit from N alone, or addition of I when disease is inadequately controlled by N alone, however most pts have limited benefit from ICI. More effective therapeutic options are needed for the majority of people with rare variant renal cell carcinomas. Novel markers of response are required to more rapidly predict pts who will progress on N. Translational research to identify predictive biomarkers of response is ongoing. Clinical trial information: NCT03177239.
Association of opioid use with response to immune checkpoint inhibitors.
Authors: Michael Weinfeld, Heidy Wang, Li C. Liu, Mary Pasquinelli, Michael Huber, Lawrence Eric Feldman, Frank Weinberg
Journal: Journal of Clinical Oncology (2022)

e14595 Background: Management of cancer-related pain with opioids is hypothesized to decrease efficacy of immune checkpoint inhibitors (ICIs) through immunosuppressive effects of opioids, such as down-regulation of major histocompatibility complex class II. There is limited evidence on how opioids affect outcomes in patients receiving ICIs. Methods: We identified 212 patients at the University of Illinois Hospital and Health Sciences System who received an ICI between January 1, 2015 and July 31, 2021. Overall survival (OS) and progression-free survival (PFS) were compared in patients who were not treated with opioids, patients treated with low-dose opioids (defined as less than 60 morphine milliequivalents per day), and patients treated with high-dose opioids (defined as at least 60 morphine milliequivalents per day). Results: Out of 212 patients who received an ICI, 98 (46.2%) received no opioids, 69 (32.6%) received low-dose opioids, and 45 (21.2%) received high-dose opioids. Among all patients, 105 (49.5%) died during the study duration. The overall median survival time was 23 (95% CI = 16, 38) months for the entire sample. Patients who received opioids at any dose had a median OS of 17 months compared to 37 months in those who received no opioids (HR = 1.53, p = 0.0385). When patients receiving opioids were further divided by dose, survival time was highest in those receiving no opioids, next highest in those receiving low-dose opioids, and lowest in those receiving high-dose opioids (37 months vs 18 months vs 10 months, p = 0.0515). Among all 212 patients, progression of disease occurred in 84 (39.6%) patients. The overall median time-to-progression was 24 months. There was no significant difference in median PFS between those treated with opioids (36 months) versus not (23 months, p = 0.156). Conclusions: We observed an association between opioid therapy, especially at higher doses, and decreased median OS in patients receiving ICIs. On the other hand, there was no statistical association between opioid therapy and median PFS. These data highlight a potential drug interaction in oncology care, and further analysis looking at duration of opioid use and ECOG PS is planned.[Table: see text]
Immuno-senescence and elevated central carbon metabolism in hematopoietic stem cell compartment upon aging.
Authors: Laura Beiro-Poisa, Jonathan J.M. Landry, Anthony D. Ho
Journal: Journal of Clinical Oncology (2022)

e24030 Background: Aging is associated with decline of hematopoiesis, compromised innate immunity, and propensity for malignancies. Aging of the hematopoietic stem and progenitor cell (HSPC) compartment is caused by accumulation of senescent cells and elimination of the latter rejuvenates innate immunity in animal models. Methods: HSC (CD34+) were isolated from the bone marrow of healthy human subjects (age range 20 – 74 years; n = 18) and separated by FACS in 3 distinct subsets with high, intermediate, and low glucose uptake (GU) capacity (GU high , GU inter , GU low ). Single-cell RNA-sequencing (scRNAseq) studies, followed by gene ontology (GO) analysis of biological processes, analysis of cell cycle, and gene set enrichment analysis (GSEA) were performed. Results: While the percentages of GU inter and GU low subpopulations remain relatively constant with age, the proportion of GU high subset increases continuously with age (from 0.2% in adults &lt; 30 years to 6,7% in &gt; 60 years). GO analysis revealed that the GU high subset showed a significantly higher expression of genes involved in myeloid development, cell cycle arrest, inflammation and stress response, apoptosis, and significantly lower expressions of genes involved in lymphoid development. GSEA confirmed that the gene sets for cell cycle arrest, senescence associated secretory phenotype (SASP), anti-apoptosis/survival and P53 pathways are significantly up-regulated in the GU high subset. The latter shows therefore all deregulations that are inherent hallmarks of senescence. Most of the molecular deregulations are similar to those found in murine models of aging, but there are significant differences. In addition, cell cycle analysis revealed that the proportion of cells in the G1 phase was significantly reduced in the GU high subset. Comparing the frequencies of old to young GU high , GU low cells along the cell cycle progression ranks showed a significant depletion of cells in late G1 phase among GU high cells but not in the other subsets. The frequencies of non-cycling cells in the GU low subset have remained high (&gt; 70%) irrespective of age, thus providing evidence for the quiescence status of the GU low subset, as well as for persistence of HSPC with “young phenotype”. Conclusions: Our series of proteome and single cell transcriptome analyses have shown that the GU high subpopulation is highly enriched in senescent HSPCs. This property may be exploited to enrich, visualize, and trace senescence in human bone marrow. Cell cycle analysis has revealed a significantly shortened G1 phase that is linked to dedifferentiated state in the senescent HSPC. Our results indicate a dependency of senescent HSPCs on elevated glucose metabolism as well as on anti-apoptotic factors for survival. These may represent ideal targets for elimination of senescent HSPC to restore innate immunity as demonstrated in murine models.
DUBLIN-3 results on quality of life (QoL) in second/third-line EGFR-wild type NSCLC patients (pts) receiving docetaxel (Doc) with or without plinabulin (Plin) using the validated EORTC QLQ C30 and QLQ LC13 questionnaires.
Authors: Trevor Feinstein, Stephan Ogenstad, Dominic Mitchell, Lan Huang, Ramon W. Mohanlal
Journal: Journal of Clinical Oncology (2022)

9091 Background: Plin, a novel immune-enhancing small molecule, enhances dendritic cell maturation and T-cell proliferation. In the ITT population, the Plin/Doc combination had superior Efficacy (mOS; p = 0.0399), Safety (Gr3/4 AE rate/pt/year; p = 0.038) and QTWiST (p = 0.026) vs standard of care (SoC) Doc alone in NSCLC pts in DUBLIN-3 (Han, ESMO 2021). Here we report DUBLIN-3 QoL results. Methods: DUBLIN-3(NCT02504489) was a randomized, single-blinded (pts only), active-controlled Ph3 study in 2 nd /3 rd line stage IIIB/IV, EGFR wt NSCLC pts with a measurable lesion (RECIST 1.1) in the lung, and ECOG ≤ 2, conducted in US, Australia, and China. Pts (n = 559) were randomized 1:1 to Plin/Doc or Doc/Placebo (21-day (D) cycle). Doc (75 mg/m 2 on D1 and Plin 30 mg/m 2 on D1 and D8 were given by IV infusion. QoL was evaluated by the validated questionnaires EORTC QLQ C30 and QLQ LC13 (which is specific for Lung Cancer), and patient-reported scores were collected at baseline and D1, D8 of each cycle (C). Results: Baseline characteristics and QLQ C30 and LC13 scores were comparable between both groups. Plin/Doc was well tolerated. Cumulative C30 sand LC13 scores were calculated for each patient. Mean (SEM) change from baseline in cumulative C30 and LC13 scores were comparable for Plin/Doc and Doc in the first 10 cycles, however separated after C10 in favor of Plin/Doc (table). LC13 items in favor of Plin/Doc vs Doc alone, were items 31 (Coughing; p &lt; 0.05), 36 (Sore Mouth; p &lt; 0.01), 37 (Dysphagia; p &lt; 0.01). Conclusions: We previously reported an OS, Safety, and QTWiST benefit with Plin/Doc vs Doc alone (ESMO 2021) in EGFR wild type 2 nd /3 rd line NSCLC pts from DUBLIN-3. Here, we report statistically significant QoL benefits with Plin/Doc vs Doc alone, as assessed with EORTC QLQ C30 and LC13, which may be relevant to guide treatment decisions in this generally sick patient population. Clinical trial information: NCT02504489. [Table: see text]